Nanoparticles for immunotherapy
Nanoparticles that activate complement in the absence of biological molecules are described. The nanoparticles are shown to specifically target antigen presenting cells in specifically in lymph nodes, without the use of a biological molecule for targeting. These particles are useful vehicles for delivering immunotherapeutics. Surface chemistries and chemical formulations for the nanoparticles are described.
1. A medical composition for introduction into a mammal comprising:
a collection of synthetic nanoparticles that have a mean particle diameter of less than about 70 nm, wherein the nanoparticles comprise an antigen and a synthetic polymer with functional groups disposed on an exterior of the nanoparticle that activate complement in a mammal wherein the antigen is bound to the synthetic polymer with a disulfide bond, and the synthetic polymer comprises a polymer selected from the group consisting of poly(ethylene glycol)-bl-poly(propylene glycol)-bl-poly(ethylene glycol), poly(propylene sulfide), and an amphiphillic poly(propylene sulfide) block copolymer.
2. The composition of claim 1 , wherein the functional groups comprise nucleophilic groups.
3. The composition of claim 1 , wherein the functional groups comprise hydroxyls and/or thiols.
4. The composition of claim 1 , wherein the nanoparticles are micelles.
5. The composition of claim 4 , further comprising a therapeutic agent encapsulated with the micelle.
6. The composition of claim 1 , wherein the composition is free of an adjuvant other than the synthetic polymer.
7. The composition of claim 1 , wherein the functional groups induce a Th-1 response in a mammal.
8. The composition of claim 1 , wherein antigen is a peptide conjugated to the nanoparticles by the disulfide bond.
9. The composition of claim 1 , wherein the collection further comprises a biomolecule danger signal conjugated to the nanoparticles by a further disulfide bond.
10. The composition of claim 1 , further comprising a hydrophobic danger signal.
11. The composition of claim 1 , wherein the antigen is a tumor antigen or an antigen of an infectious disease.
12. The composition of claim 1 , wherein the nanoparticles further comprise a danger signal selected from the group consisting of inflammatory cytokines and ligands for Toll-like receptors.
13. The composition of claim 1 , wherein the nanoparticles are free of targeting ligands that specifically bind to a cell, the antigen is an antigen for tumor immunotherapy or infectious disease, and further comprising a danger signal chosen from the group consisting of inflammatory cytokines and ligands for Toll-like receptors.
14. The composition of claim 1 , wherein the synthetic polymer comprises a hydrophobic core and a hydrophilic corona, wherein the core is comprised of poly(propylene sulfide) and the hydrophilic corona is comprised of polyethylene glycol, and wherein the functional groups comprise nucleophiles.
15. The composition of claim 14 , wherein the nucleophiles comprise hydroxyls and/or thiols and the antigen comprises Caspase-8, MAGE-1, Tyrosinase, HER-2/neu, MUC-1 or survivin.
16. The composition of claim 1 , wherein the nanoparticles further comprise an immunosuppressant.
17. An immunostimulatory composition for introduction into a patient that comprises a collection of synthetic nanoparticles that have a mean particle diameter of less than about 70 nm, wherein the nanoparticles comprise an antigen and a synthetic polymer, wherein the antigen is bound to the synthetic polymer with a disulfide bond, and the synthetic polymer comprises a polymer selected from the group consisting of poly(ethylene glycol)-bl-poly(propylene glycol)-bl-poly(ethylene glycol), poly(propylene sulfide), and an amphiphillic poly(propylene sulfide) block copolymer, with the composition inducing an immune response against the antigen in the patent without inducing a TNF-alpha response and without inducing an IL-6 response.
18. The composition of claim 17 , wherein the nanoparticles are free of targeting ligands that specifically bind to a cell, and the antigen is an antigen of a tumor or an infectious disease.
19. The composition of claim 17 , wherein the nanoparticles further comprise an immunosuppressant.
20. The composition of claim 17 , wherein the synthetic polymer comprises a core and a hydrophilic corona, wherein the core is comprised of poly(propylene sulfide) and the hydrophilic corona is comprised of polyethylene glycol.
21. A method of transfecting a cell in a lymph node of a patient comprising:
administering to a mucosal surface of a patient, under mild pressure, a collection of synthetic nanoparticles that have a mean particle diameter of less than about 70 nm, wherein the nanoparticles comprise an antigen and a synthetic polymer, wherein the antigen is bound to the synthetic polymer with a disulfide bond, and the synthetic polymer comprises a polymer selected from the group consisting of poly(ethylene glycol)-bl-poly(propylene glycol)-bl-poly(ethylene glycol), poly(propylene sulfide), and an amphiphillic poly(propylene sulfide) block copolymer.
22. A method of inducing a Th1-mediated immunological response to an antigen that involves toll-like receptor TLR4 in a patient without inducing a TNF-alpha response and without inducing an IL-6 response comprising
introducing into the patient a pharmaceutically acceptable composition comprising a collection of synthetic nanoparticles that
have a mean particle diameter of less than about 70 nm and
comprise the antigen and a synthetic polymer, wherein the antigen is bound to the synthetic polymer with a disulfide bond, and the synthetic polymer comprises a polymer selected from the group consisting of poly(ethylene glycol)-bl-poly(propylene glycol)-bl-poly(ethylene glycol), poly(propylene sulfide), and an amphiphillic poly(propylene sulfide) block copolymer,
with the composition inducing an immune response against the antigen in the patent without inducing a TNF-alpha response and without inducing an IL-6 response.
23. The method of claim 22 , wherein the nanoparticles are free of targeting ligands that specifically bind to a target cell, and the antigen is an antigen of a tumor or an infectious disease.
24. The method of claim 22 , wherein the nanoparticles comprise a core and a hydrophilic corona, wherein the core is comprised of poly(propylene sulfide) and the hydrophilic corona is comprised of a synthetic polymer that comprises polyethylene glycol and nucleophilic functional groups.
25. The method of claim 22 , wherein the nanoparticles further comprise an immunosuppressant.
26. The composition of claim 1 , wherein the synthetic polymer is an amphiphillic poly(propylene sulfide) block copolymer.